Structurally and mechanistically novel probes of deacetylase enzymes

Histone deacetylases (HDACs) have emerged as valuable targets for small-molecule probes and drugs due to their fundamental role in transcriptional regulation and implication in several diseases. Much effort has been placed on structure-aided design for inhibitors of the HDAC active site, though limited progress has been made towards developing inhibitors selective for individual isoforms. High-throughput and unbiased screens to discover novel molecular scaffolds will be critical for developing a collection of isoform-selective small molecules, which would enable investigators to probe the function of individual isoforms in different cellular and medical contexts. Our group has an interest in elucidating the relevant cellular functions and substrates for various Class IIa HDACs with an emphasis on non-histone substrates, including transcription factors. Our group combines direct binding assays with biochemical and cellular assays to identify HDAC modulators with novel chemical structures, selectivity patterns, or mechanisms of action unrelated to deacetylase activity.

BRD2577

Structures of novel deacetylase inhibitors with varying selectivity patterns